1. Field of the Invention
The invention relates to agonists of the G protein-coupled receptor TGR5, compositions comprising them, methods of making the compounds and compositions and using them for the treatment of diseases TGR5 mediates or is implicated in.
2. Summary of the Related Art
Bile acids play essential roles in the absorption of dietary lipids and in the regulation of bile acid biosynthesis. While bile acids have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for bile acids as signaling molecules has emerged. Bile acids activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5, and activate nuclear hormone receptors such as farnesoid X receptor a (FXR-α). Through activation of these diverse signaling pathways, bile acids can regulate their own enterohepatic circulation, but also triglyceride, cholesterol, energy, and glucose homeostasis. Thus, bile acid (BA) controlled signaling pathways are promising novel drug targets to treat common metabolic diseases, such as obesity, type II diabetes, hyperlipidemia, and atherosclerosis. Houten et al., The EMBO Journal (2006) 25, 1419-1425).
Watanabe et al., Nature 2006, 439 (7075) 484-489 showed that the administration of bile acids to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of bile acids is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2−/− mice. Treatment of brown adipocytes and human skeletal myocytes with bile acids increases D2 activity and oxygen consumption. These effects are independent of FXR-a, and instead are mediated by increased cAMP production that stems from the binding of bile acids with TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signaling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.
Glucagon-like peptide-1 (GLP-1) is produced by L-cells in the distal digestive tract and affects multiple metabolic parameters, including enhanced insulin secretion, glucagon suppression, and lowering of blood glucose. TGR5 expression in L-cells is linked to increased GLP-1 secretion. Katsuma, et al., Biochem. Biophys. Res. Commun. 2005, 329 (1), 386-390) showed that bile acids promote glucagon-like peptide-1 (GLP-1) secretion through TGR5 in a murine enteroendocrine cell line STC-1. RNA interference experiments showed that reduced expression of TGR5 resulted in reduced secretion of GLP-1. Furthermore, transient transfection of STC-1 cells with an expression plasmid containing TGR5 significantly enhanced GLP-1 secretion.
TGR5 and modulators of it have been the subject of a several patent applications:
WO/2008/097976—Heterocyclic Modulators of TGR5 for Treatment of Disease
WO/2008/091540—Substituted Bile Acids as TGR5 Modulators and Methods of Use
WO/2008/067219—Quinazolinone Modulators of TGR5
WO/2008/067222—Heterocyclic Modulators of TGR5
WO/2004/067008—Receptor Agonists
WO/2004/043468—Screening Method
US 2006/0199795—Receptor Agonists
US 2008/0031968—Methods for Increasing Cellular Energy Expenditure